Team
OncoRib
Team manager: Plisson-Chastang Célia
Presentation
We want to characterize the links between ribosomes and cell fate, in normal and pathological conditions.
Ribosomes are universal molecular machines that translate mRNA into proteins. Recent findings show how through both their final function and their assembly process, they lay at the center of gene regulation, cell fate and homeostasis. With an integrated approach combining structural and functional methodologies, our aim is to characterize the links between ribosomes and cell fate in normal and pathogenic conditions, especially during cancer mechanisms. Our overall goal is to provide a fundamental description of these oncogenic processes, in the optics of delivering new prognostic markers or therapeutic strategies for particular cancer types.
Project 1
Ribosomes have long been thought to harbor strictly identical composition and production capacities for each cell of an organism. However, many different findings have brought nuances to this somehow monolithic view, and it is now clearly established that compositional heterogeneity of ribosomes is responsible for regulating the translation of certain mRNAs, which can, in turn, directly influence cell fate. In recent years, somatic mutations of ribosomal proteins have been clearly identified as oncogenic factors. This underlines the importance of characterizing ribosomal particles production and activity, in normal and pathological conditions, to understand the impact of ribosomes in cancer mechanisms.
In order to understand how these mutations can trigger oncogenic effects, we particularly focus our studies on ribosomes harboring either point mutations of the C-terminal domain of RPS15, which are frequently found in patients suffering from Chronic Lymphocytoc Leukemia (CLL), or deletion of RPL22, retrieved in T-cell acute Lymphoid Leukemia (T-ALL), as well as in endometrial, colorectal and gastric cancers. We combine cryo-EM assays with biochemical and functional analyses as well as multi-omics approaches to understand whether and how these mutant, “onco-ribosomes” can translate cancer processes.
Project 2
Cancer cells are dependent on robust ribosome production to maintain their proliferative capacity. A number of chemotherapeutic agents have been observed to impede ribosome production, which is perceived by cells as “nucleolar stress” (NS). This triggers a range of response pathways, both p53-dependent and independent, which ultimately result in either cell cycle arrest or apoptosis. The 5S RNP particle, which constitutes a subcomplex of the ribosomal particle, plays a pivotal role in the NS response. In the event of defects in the assembly of ribosomes, 5S RNP particles accumulate in a free form. One of the most thoroughly researched molecular functions of these free 5S is to sequester and inhibit MDM2, thus promoting p53 stabilisation. These particles are of great significance with regard to the development of cancer and the response of tumours to chemotherapies. They are also relevant to a group of rare genetic diseases, which are collectively known as ribosomopathies.
Our objective is to elucidate the molecular functions of these 5S particles within cells, their regulation, and the potential for targeting these particles for innovative therapies. To achieve this, we are employing a multidisciplinary approach, combining yeast to human cell line models with biochemical and structural characterisation in vitro, facilitated by the expertise in cryo-EM within our team. In the course of this project, we have recently identified a new partner of these particles, SURF2, that participates in 5S RNP regulation, and we are actively characterizing its role (Tagnères et al., 2024)
– Tagnères S, Santo PE, Radermecker J, Rinaldi D, Froment C, Provost Q, Bongers M, Capeille S, Watkins N, Marcoux J, Gleizes PE, Marcel V, Plisson-Chastang C, Lebaron S. SURF2 is a MDM2 antagonist in triggering the nucleolar stress response. Nat Commun. 2024 Sep 27;15(1):8404. doi: 10.1038/s41467-024-52659-x.
– Khreiss A, Capeyrou R, Lebaron S, Albert B, Bohnsack KE, Bohnsack MT, Henry Y, Henras AK, Humbert O. The DEAD-box protein Dbp6 is an ATPase and RNA annealase interacting with the peptidyl transferase center (PTC) of the ribosome. Nucleic Acids Research 2023 Jan
– Dos Santos Morais R, Santo PE, Ley M, Schelcher C, Abel Y, Plassart L, Deslignière E, Chagot ME, Quinternet M, Paiva ACF, Hessmann S, Morellet N, M F Sousa P, Vandermoere F, Bertrand E, Charpentier B, Bandeiras TM, Plisson-Chastang C, Verheggen C, Cianférani S, Manival X. Deciphering cellular and molecular determinants of human DPCD protein in complex with RUVBL1/RUVBL2 AAA-ATPases J Mol Biol . 2022 Oct 434(19):167760
– Bortolin-Cavaillé ML, Aurélie Q, Supuni TG, Thomas JM, Sas-Chen A, Sharma S, Plisson-Chastang C, Vandel L, Blader P, Lafontaine DLJ, Schwartz S, Meier JL, Cavaillé J. Probing small ribosomal subunit RNA helix 45 acetylation across eukaryotic evolution Nucleic Acids Res. 2022 Jun 1:gkac404. doi: 10.1093/nar/gkac404. Online ahead of print. PMID: 35648437
– Lebaron S, O’Donohue MF, Smith SC, Engleman KL, Juusola J, Safina NP, Thiffault I, Saunders CJ, Gleizes PE. Functionally impaired RPL8 variants associated with Diamond-Blackfan anemia and a Diamond-Blackfan anemia-like phenotype Hum Mutat, 43:389-402 2022 Mar
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